PT88830B - PROCESS FOR THE PREVENTION OF FORMATION OF BLOOD COAGULATES IN THE EXTRA-CORPORAL CIRCUIT OF DIALYSIS AND COMPOSITION APPARATUS FOR THE SAME - Google Patents
PROCESS FOR THE PREVENTION OF FORMATION OF BLOOD COAGULATES IN THE EXTRA-CORPORAL CIRCUIT OF DIALYSIS AND COMPOSITION APPARATUS FOR THE SAME Download PDFInfo
- Publication number
- PT88830B PT88830B PT88830A PT8883088A PT88830B PT 88830 B PT88830 B PT 88830B PT 88830 A PT88830 A PT 88830A PT 8883088 A PT8883088 A PT 8883088A PT 88830 B PT88830 B PT 88830B
- Authority
- PT
- Portugal
- Prior art keywords
- defibrotide
- extra
- dialysis
- process according
- corporal
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3672—Means preventing coagulation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3672—Means preventing coagulation
- A61M1/3675—Deactivation
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Anesthesiology (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- External Artificial Organs (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
DESCRIÇÃO DO INVENTODESCRIPTION OF THE INVENTION
O presente invento refere-se a hemodiálise, ou dialise extra-corporal, e mais especificamente a um processo para impedir a formação de coágulos de sangue no circuito extra-corporal do aparelho de hemodiálise.The present invention relates to hemodialysis, or extra-corporal dialysis, and more specifically to a process to prevent the formation of blood clots in the extra-corporal circuit of the hemodialysis device.
Constitui também um objecto do presente invento a utiIt is also an object of the present invention to use
Λ lização de uma substancia activa especifica, sob a forma de uma composição, para uma tal acção preventiva.Use of a specific active substance, in the form of a composition, for such a preventive action.
A hemodiálise, ou diálise extra-corporal, e um instru.Hemodialysis, or extra-corporal dialysis, is an instruction.
Λ r mento terapêutico largamente utilizado na pratica hospitalar,Therapeutic instrument widely used in hospital practice,
Λ X e assegura a sobrevivência diaria de milhares de pessoas queΛ X and ensures the daily survival of thousands of people who
Λ f sofrem de insuficiência renal crónica.Λ f suffer from chronic kidney failure.
A hemodiálise e, alem disso, aplicada também no tratamento de doentes que, quer acidentalmente quer voluntariamente, tomaram venenos ou uma quantidade excessiva de drogas.Hemodialysis is also applied to the treatment of patients who, either accidentally or voluntarily, have taken poisons or an excessive amount of drugs.
Z Z ΛZ Z Λ
Esta técnica e essencialmente baseada na transferencia dos solutos dissolvidos no sangue, através de uma membrana semi-permeével, para o líquido de lavagem ou líquido de diélise que corre para o outro lado da membrana em sentido contra -corrente em relação ao fluxo de sangue.This technique is essentially based on the transfer of the solutes dissolved in the blood, through a semi-permeable membrane, to the washing liquid or dialysis liquid that runs to the other side of the membrane in a counter-current direction in relation to the blood flow.
Λ SΛ S
Estes solutos são, obviamente, substancias que sio toxicas ou a presença das quais no sangue e de qualquer forma indesejada ou excessiva.These solutes are, of course, substances that are toxic or the presence of which in the blood is in any way undesirable or excessive.
A dita tranferencia, efectua-se a uma velocidade que é proporcional aos gradientes de concentração existentes para os ditos solutos entre os dois líquidos; consequentemente, o produto/catabõlismc celular migrara através da membrana para a solução de lavagem e, inversamente, as substancias dissolvidas no liquido acima, tais como, por exemplo, glucose ou diversos electrolitos, passarão para o sangue.Said transference, takes place at a speed that is proportional to the concentration gradients existing for said solutes between the two liquids; consequently, the cellular product / catabolism will migrate across the membrane into the washing solution and, conversely, substances dissolved in the above liquid, such as, for example, glucose or various electrolytes, will pass into the blood.
aparelho pare executar a dialise extra-corporal es ta apresentado esquematicamente na figura 1.device to perform extra-corporal dialysis is shown schematically in figure 1.
sangue e tirado da veia ou do shunt arterio-venoso dos doentes e através de uma bomba C e conduzido a um apare68 363blood is taken from the vein or arterio-venous shunt of the patients and through a C pump and conducted to an apparatus68 363
Ref: 88 OT 37 ERef: 88 OT 37 E
Iho de diálise D e depois passado através de um filtro E tendo também a função de captar e reter ar ou bolhas de gas.Dialysis eye D and then passed through a filter E also having the function of capturing and retaining air or gas bubbles.
sangue, apos ser dialisado e filtrado, volta então para o circuito corporal. Durante a diálise é importante evitar a coagulação do sangue no circuita extra-corporal, em primeiro lugar porque o sangue do paciente ficaria desta forma com poucos eritrócitos. Em segundo lugar, os poros da membrana ficariam progressivamente obstruídos por estes coágulos e a continuidade da operação seria impossível.blood, after being dialysed and filtered, then returns to the body circuit. During dialysis, it is important to avoid blood clotting in the extra-bodily circuit, primarily because the patient's blood would be left with few red blood cells. Second, the membrane pores would be progressively clogged by these clots and continuity of the operation would be impossible.
Até a data, para obviar este inconveniente, tem sidoTo date, to remedy this inconvenience, it has been
Λ adicionado ao sangue, no circuito extra-corporal, uma substan. cia adequada para impedir a sua coagulação.A substance is added to the blood in the extra-corporal circuit. adequate to prevent its clotting.
A substancia que e mais frequentemente usada á a heparina em dosagens entre 5.D0D e 10.000 unidades.The substance that is most often used is heparin in dosages between 5.D0D and 10,000 units.
A heparina e administrada segundo duas vias diferentes e igualmente eficazes:Heparin is administered in two different and equally effective ways:
a) uma injecção inicial efectuada simultaneamente com o inicio da diálise num ponto do tubo que conduz o sangue do paciente para o aparelho de diálise (ponto A na figura 1), usando uma quantidade de heparina correspondendo a metade do total a ser administrado. Esta primeira administração á seguida de outras duas administrações, com intervalos de 1,30 horas, com doses de heparina correspondendo cada uma a um quarto do total.a) an initial injection performed simultaneously with the initiation of dialysis at a point on the tube that conducts the patient's blood to the dialysis device (point A in figure 1), using an amount of heparin corresponding to half of the total to be administered. This first administration is followed by two other administrations, at intervals of 1.30 hours, with doses of heparin each corresponding to a quarter of the total.
b) De uma forma continua, diluindo heparina numvolu me adequado de solução fisiológica, geralmente 250 ml, e ligando o frasco B (figura l) ao tubo de condução atrás meneio nado.b) Continuously, diluting heparin in an appropriate volume of physiological solution, usually 250 ml, and connecting vial B (figure 1) to the conduction tube above mentioned.
Contudo, esta substancia tem parâmetros e áreas de distribuição diferentes no corpo humano, pelo que é possível que, voltando para a circulação através da linfa, a heparina tenha um efeito anti-còagulante para os doentes durante algumas horas após a diálise.However, this substance has different parameters and distribution areas in the human body, so it is possible that, returning to the circulation through the lymph, heparin has an anti-clotting effect for patients for a few hours after dialysis.
Por esta razão devem ser avaliados os tempos de coa68 363For this reason, the coa68 times 363
Ref: 88 OT 37 ΕRef: 88 OT 37 Ε
gulação nas pacientes submetidos a dialise sob as condições acima indicadas, tanto algum tempo apos a dialise como a períodos de tempo determinados.regulation in patients undergoing dialysis under the conditions indicated above, both some time after dialysis and at certain periods of time.
ΛΛ
Dependendo dos valores deste parametro são então adrni nistrados, consequentemente, doses de um antidoto da heparina, nomeadamente a protamina.Depending on the values of this parameter, doses of a heparin antidote, namely protamine, are then administered.
Além disso no doente em que ha uma contra-indicação no que se refere ao prolongamento do tempo de coagulação (por exemplo, devido a traumas, intervenções cirúrgicas, queimaduras recentes e uma anamenese que pode estar relacionada com ulceras sangrantes), o uso da técnica acima descrita tem, evi. dentemente, riscos relevantes.In addition, in the patient who has a contraindication with regard to prolonged clotting time (for example, due to trauma, surgical interventions, recent burns and an anamnesis that may be related to bleeding ulcers), the use of the technique described above has, evi. relevant risks.
Alternativamente, nestas circunstancias, .pode-se usar a dialise peritoneal a qual, embora versátil e sob alguns pon. tos de vista menos complexa, que a técnica acima, tem igualmente alguns limites de utilização. Por exemplo, não pode ser usada em doentes que foram submetidos a intervenção cirúr gica abdominal recente.Alternatively, in these circumstances, one can use peritoneal dialysis which, although versatile and under some points. less complex views, than the above technique, also has some limits of use. For example, it cannot be used in patients who have undergone recent abdominal surgery.
Em resumo, embora ja usada ha diversos anos, o uso de heparina na hemodiálise, como ja mencionado, possui diversas inconvenientes.In summary, although used for several years, the use of heparin in hemodialysis, as already mentioned, has several drawbacks.
Por último, não s'e deve esquecer que este anti-coagulante pode também induzir nos doentes dialisados uma ligeira forma de anemia provocada por perdas sanguíneas a nivel do tu bo digestivo.Finally, you should not forget that this anticoagulant can also induce a mild form of anemia in dialysis patients caused by blood loss in the digestive tube.
Para resolver estes problemas, tem sido recentemente proposto o uso de ticlopidina, uma droga anti-agregante piaquetaria, como substituto parcial ou total da heparina.To solve these problems, it has recently been proposed to use ticlopidine, an anti-aggregating drug from piaquetaria, as a partial or total substitute for heparin.
Esta droga é administrada por via oral em doses entre 250 e 500 mg/Kg. Os resultados obtidos ate à data não são conclusivos: por um lado, de facto, tem sido evidenciada a possibilidade de substituir totalmente a heparina com ticlopidiná: (Mion C. e col. Haemodialysis without heparin, a possible benefit from the use of ticlopidine in end stage re.This drug is administered orally in doses between 250 and 500 mg / kg. The results obtained to date are not conclusive: on the one hand, in fact, the possibility of completely replacing heparin with ticlopidine has been evidenced: (Mion C. et al. Haemodialysis without heparin, a possible benefit from the use of ticlopidine in end stage re.
363363
Ref: 88 DT 37 ERef: 88 DT 37 E
nal disease haemodialysis patients Thrombos. and Haemostas.nal disease haemodialysis patients Thrombos. and Haemostas.
46. 262, 1981), enquanto que, por outro lado, tem-se observado que sob condições idênticas as experimentais, a droga não foi capaz de impedir a deposição de coágulos de sangue na mem brana do aparelho de dialise(Rajah 5.M. e col.’’”Evaluation of five antiplatelet regimens in haemodialysis: prevention of platelet deposition and thrombus formation Thrombos. and Haia mostas. .50, 61, 1983).46. 262, 1981), while, on the other hand, it has been observed that under conditions identical to the experimental ones, the drug was not able to prevent the deposition of blood clots in the dialysis device membrane (Rajah 5.M . et al. '' ”Evaluation of five antiplatelet regimens in haemodialysis: prevention of platelet deposition and thrombus formation. Thrombos. and The Hague most. 50, 61, 1983).
Sabe-se, alem disso que a administração regular de ticlopidina induz possíveis efeitos secundários do tipo hematológico, tal como, por exemplo, o prolongamento do tempo de he. morragia.Furthermore, it is known that the regular administration of ticlopidine induces possible side effects of the hematological type, such as, for example, the prolongation of he time. died.
Como conclusão, mesmo com esta droga parece não ser possível resolver de uma forma eficaz e definitiva as limitamencionadas , ções,acima/da hemodiálise que ocorrem utilizando heparina.In conclusion, even with this drug, it seems that it is not possible to effectively and definitively resolve the limited limitations, above / on hemodialysis that occur using heparin.
Do panorama acima, torna-se claro que a necessidade é de se poder efectuar a hemodiálise sem a consequência simultâ. nea e indesejada de alterar de qualquer forma a hemostase:' dos doentes.From the above panorama, it becomes clear that the need is for hemodialysis to be carried out without the simultaneous consequence. unwanted effect of altering hemostasis in any way: 'of patients.
Verificou-se agora, e constitui o objecto principal do presente invento, que o problema acima identificado e subs tancialmente resolvido usando o Defibrotide (D.C.I. Chronique O.M.5. 35 5 supl. 4, 1981) o qual é quimicamente definido como um polidesoxiribonucleótido obtido por extracção de orgãos animais (Patente E.U. N2 3 770 720 e 3 899 481, bem como o Pedido de Patente Europeia l\l2 87 902 502.1),.It has now been found, and is the main object of the present invention, that the problem identified above and substantially solved using Defibrotide (DCI Chronique OM5. 35 5 suppl. 4, 1981) which is chemically defined as a polydeoxyribonucleotide obtained by extraction animal organs (US Patent No. 3770720 2 and 3899481 and the European patent application l \ l 2 87 902 502.1) ,.
As propriedades farmacológicas e clínicas do Defibrotide são conhecidas, e constituem o assunto de patentes e de diversas publicações cientificas.The pharmacological and clinical properties of Defibrotide are well known, and are the subject of patents and several scientific publications.
De facto sabe-se que esta substancia e dotada de uma actividade pro-fibrinolitica relevante (Patente E.U. N2 3 8929 567 e 5. Coccheri e col.: «Effect on fibrinolysis of a new antithrombotic agent: Fraction P. (Defibrotide) Int. J. Clin. Pharm. Res. II (3) 227-245 1982)enquanto não tem qualΛ Λ quer influencia sobre os parâmetros de hemocoagulação(S. Coc.--3In fact, it is known that this substance has a relevant pro-fibrinolytic activity (EU Patent No. 2 3 8929 567 and 5. Coccheri et al .: “Effect on fibrinolysis of a new antithrombotic agent: Fraction P. (Defibrotide) Int J. Clin. Pharm. Res. II (3) 227-245 1982) while having no influence on hemocoagulation parameters (S. Coc .-- 3
363363
Ref: 8B OT 37 ERef: 8B OT 37 E
cheri, Supra; G. Prino e col: Indagini preliminari sull’atti. vità fibrinolitica, nell’animale e nell’uomo, di una nuova sostanza presente in diversi organi animali” Simposio Interna zionale HLa ricerca scientifica nell’industria farmacêutica in Italia Roma, ottabre 1975, Ferro Edizioni, Milani, 1977, pp 555-560).cheri, Supra; G. Prino et al: Indagini preliminari sull'atti. vitin fibrinolitica, nell'animale and nell'uomo, for a new sostanza present in a variety of animal organizations ”Internal Symposium H La ricerca scientifica nell'industria pharmaceutical in Italia Roma, ottabre 1975, Ferro Edizioni, Milani, 1977, pp 555-560 ).
A actividade anti-trombotica da droga tem sido o assun to de uma série de estudos (R. Niada e col: Antithrombotic activity of polydeoxyribonucleotidic substances of mammalian origin (laboratory Code Fraction P) in experimental animais. VII International Congress on thrombosis and haemostasis, Lo.n don - July 1979, Thrombos. Haemostas, 42 388 1975; G. Prino e col. Antithrombotic activity of a polydeoxyribonucleotidic - like substances (fraction P) in A. StranaAdvances in coagulation, fibrinolysis, platelet aggregation and atherosclero sis European Symposium of 5. Flavia (Palermo, October 1976) Proceedings page 282-89 CEPI Roma 1978; E. Mozzi e col Effeç. tiveness of Defibrotide for prophylaxis of deep venous thrombosis after general sur.gery: a double blind, placebo-controlled clinicai trial VIII International Congress on Thrombosis (Is. tanbul, June 1984) Defibrotide Symposium Proceedings, Haemostasis 1986, 16 Sl- 36-38; Ciavarella N. e col. :Effectiveness of Defibrotide for prophylaxis of deep venous thrombosis in gynecological surgery: a double blind placebo-controlled clinicai trial VIII International Congress on Thrombosis, Haemos tasis 1986, 16 51 39-41; A. Rizzi e col: Profilassi con Defibrotide delle trombosi venosi profonde in chirurgia toracicaThe antithrombotic activity of the drug has been the subject of a series of studies (R. Niada et al: Antithrombotic activity of polydeoxyribonucleotidic substances of mammalian origin (laboratory Code Fraction P) in experimental animals. VII International Congress on thrombosis and haemostasis, Lo.n don - July 1979, Thrombos. Haemostas, 42 388 1975; G. Prino et al. Antithrombotic activity of a polydeoxyribonucleotidic - like substances (fraction P) in A. StranaAdvances in coagulation, fibrinolysis, platelet aggregation and atherosclero sis European Symposium of 5. Flavia (Palermo, October 1976) Proceedings page 282-89 CEPI Roma 1978; E. Mozzi et al Effeç. tiveness of Defibrotide for prophylaxis of deep venous thrombosis after general sur.gery: a double blind, placebo-controlled clinical trial VIII International Congress on Thrombosis (Is. Tanbul, June 1984) Defibrotide Symposium Proceedings, Haemostasis 1986, 16 Sl- 36-38; Ciavarella N. et al.: Effectiveness of Defibrotide for prophyla xis of deep venous thrombosis in gynecological surgery: a double blind placebo-controlled clinical trial VIII International Congress on Thrombosis, Haemos tasis 1986, 16 51 39-41; A. Rizzi et al: Profilassi con Defibrotide delle trombosi venosi profonde em thoracic chirurgia
Minerva Medica 78, 11 745-750 19B7).Minerva Medica 78, 11 745-750 19B7).
Contudo, o Defibrotide não tem qualquer efeito do tipo anti-agregante plaquetário (R. Niada e col: Antithrombotic activity of a polydeoxyribonucleotidic substance extracted from animal organs; a possible link with prostacyclin Thromb. Res. 23 233-246, 1981; J.R. O'Brien e col.: The effects in humans of Defibrotide i.v. on numerous blood parameters11 7thHowever, Defibrotide has no anti-platelet-type effect (R. Niada et al: Antithrombotic activity of a polydeoxyribonucleotidic substance extracted from animal organs; a possible link with prostacyclin Thromb. Res. 23 233-246, 1981; JR O 'Brien et al .: The effects in humans of Defibrotide iv on numerous blood parameters 11 7th
6Β 3636Β 363
Ref: 88 OT 37 ERef: 88 OT 37 E
-7l-7l
International Congress on Fibrinolysis (Venice March 1984) Re. sumo n. 227, Haemostasis 14, 121, 19B4).International Congress on Fibrinolysis (Venice March 1984) Re. juice n. 227, Haemostasis 14, 121, 19B4).
As suas propriedades anti-tromboticas, como -acima mencionadas, têm sido explicadas demonstrando que a droga induz um aumento na circulação do activador de plasminogenio te. cidular (L. Mussoni e col.:Activation of plasma and vascular fibronolytic activity by a polydeoxyribonucleotidic substance, Fraction P, in rats and rabbits'’ Vllth International Congress on Thrombosis and Haemostasis (London, July 1979) Resumo 0922. Thrombos, Haemostas. 1979, 42. 388; A. Kumar e col; Endotheli al function modulation and control of vascular and thrombotic disorders: experimental results with a polydeooxyribonucleoti. de agent Defibrotide. The American society of Haematology,Its anti-thrombotic properties, as mentioned above, have been explained by demonstrating that the drug induces an increase in the circulation of the plasminogen activator te. cidular (L. Mussoni et al.: Activation of plasma and vascular fibronolytic activity by a polydeoxyribonucleotidic substance, Fraction P, in rats and rabbits '' Vllth International Congress on Thrombosis and Haemostasis (London, July 1979) Abstract 0922. Thrombos, Haemostas. 1979, 42. 388; A. Kumar et al; Endotheli al function modulation and control of vascular and thrombotic disorders: experimental results with a polydeooxyribonucleoti. By agent Defibrotide. The American society of Haematology,
2Bth Annual Meeting, December 6-9 1986, San Francisco-Califor nia, Blood 68 (5) 365A Resumo: n5.1302 1986; E.M. Pogliani e col. ; ”Studi di bióequivalenza di due schemi posologici su parametri delia fibrinolisi in soggetti volontari sani Farmaci e Terapia IV 2 1 1987) e da prostaciclina (Niada R. e col.: Antithrombotic activity of a polydeoxyribonucleotidic substance extracted from mammalian organs ver acima; G. Cizrne. ci: Corrective effect of Defibrotide on altered endothelium cell function in atherosclerosis Xth International Congress on Thrombosis and Haemostasis, July 14, 1985, Thrombos, Haemostas. 54(1) 1 372 1985).2bth Annual Meeting, December 6-9 1986, San Francisco Califor-nia, Blood 68 (5) 365A Abstract n 5 .1302 1986; EM Pogliani et al. ; ”Studi di bióequivalenza di due schemi posologici su parametri delia fibrinolisi in soggetti volontari sani Farmaci e Terapia IV 2 1 1987) and prostacyclin (Niada R. et al .: Antithrombotic activity of a polydeoxyribonucleotidic substance produced from mammalian organs see above; G. Cizrne. Ci: Corrective effect of Defibrotide on altered endothelium cell function in atherosclerosis Xth International Congress on Thrombosis and Haemostasis, July 14, 1985, Thrombos, Haemostas. 54 (1) 1 372 1985).
Das publicações acima citadas torna-se evidente que a falta de actividade anti-agregante plaquetária e de influΛ Λ encia sobre os parâmetros de hemocoagulação apresentados pelo Defibrotide juntamente com a sua : erficacia anti-trombotica e pró-fibrinolitica demonstrada, deve, possivelmente, sugerir somente o uso, do próprio Defibrotide no que diz respeito à eliminação de coágulos de sangue ja formados.From the aforementioned publications, it is evident that the lack of anti-platelet aggregating activity and influence on the hemocoagulation parameters presented by Defibrotide together with its demonstrated anti-thrombotic and pro-fibrinolytic erficacy, should possibly suggest only the use of Defibrotide itself with regard to the elimination of already formed blood clots.
Pelo contrario, sera posto em evidencia, a partir das considerações que se seguem e dos testes experimentais já efectua. dos, o facto que e mais surpreendente no presente invento, á o queOn the contrary, it will be highlighted, based on the following considerations and the experimental tests already carried out. the fact that is more surprising in the present invention is what
363363
Ref: 88 OT 37 ERef: 88 OT 37 E
-8consiste na introdução do Defibrotide no inicio do tratamento-8 consists of the introduction of Defibrotide at the start of treatment
Ζ Λ x de dialise, nomeadamente de forma simultanea.com o inicia do fluxo de sangue tomado a partir do doente para o circuito extra-corporal, cuja introdução e efectuada a montante do aparelho de dialise e do filtro (figura l), de preferencia a mon tante da bomba de circulação, que tem mostrado ser completa mente eficaz em impedir fenomenos de coagulação no sangue noΛ Λ x of dialysis, namely simultaneously with the initiation of the blood flow taken from the patient to the extra-corporal circuit, the introduction of which is carried out upstream of the dialysis device and the filter (figure 1), preferably the amount of the circulation pump, which has been shown to be completely effective in preventing blood clotting phenomena in the
Λ circuito extra-corporal, evitando simultaneamente os inconvenientes encontrados com a heparina e com as outras drogas, prinExtra extra-body circuit, while avoiding the inconveniences found with heparin and other drugs, mainly
Λ cipalmente a acção sobre os parâmetros da hemocoagulação.It is mainly the action on the hemocoagulation parameters.
Além disso, um facto peculiar sobre o uso da droga nes.In addition, a peculiar fact about the use of the drug nes.
Λ Z te sistema terapêutico e que a actividade do Defibrotide em impedir os fenomenos da coagulação no circuito extra-corporal ocorre, de forma diferente da heparina, com doses diferentes dependendo da via de administração usada. Mais particularmente, verificou-se, e constitui outra objecto do presente inven. to, que a eficacia do Defibrotide nesta aplicação terapêutica e evidente em doses mais baixas para a administração em bolus” (processo A” como acima descrito para a Heparina) em relação à infusão contínua (processo B”).Λ z the therapeutic system and that the activity of Defibrotide in preventing coagulation phenomena in the extra-corporal circuit occurs, differently from heparin, with different doses depending on the route of administration used. More particularly, it has been found, and is another object of the present invention. Therefore, the effectiveness of Defibrotide in this therapeutic application is evident in lower doses for bolus administration ”(process A” as described above for Heparin) in relation to continuous infusion (process B ”).
De novo em relação ao objecto do presente invento, o Defibrotide foi inicialmente usado num grupo de 9 doentes a fazer tratamentos de dialise com uma frequência de tres vezes por semana. A droga foi administrada de acordo com o processo A” como acima descrito em relação à heparina. Mais precisamen. te, no inicio da dialise foram injectados 2,5 ml de solução contendo 200 mg de substancia; repetiu-se a mesma dose apés 1,5-2 horas.Again in relation to the object of the present invention, Defibrotide was initially used in a group of 9 patients undergoing dialysis treatments at a frequency of three times a week. The drug was administered according to procedure A ”as described above in relation to heparin. They need more. te, at the beginning of dialysis 2.5 ml of solution containing 200 mg of substance were injected; the same dose was repeated after 1.5-2 hours.
No final da primeira semana de tratamento, para um total de 9 tratamentos de dialise por doente, como não se verificaram nenhuns inconvenientes de qualquer tipo em relação a circulação do sangue no dispositivo, o teste experimental foi alargado a um maior numero de doentes.At the end of the first week of treatment, for a total of 9 dialysis treatments per patient, as there were no inconveniences of any kind in relation to blood circulation in the device, the experimental test was extended to a larger number of patients.
Trataram-se, deste modo, 54 doentes. Verificou-se,In this way, 54 patients were treated. It was found,
363363
Ref: 88 ΟΤ 37 ΕRef: 88 ΟΤ 37 Ε
ζ ζ ζ nalguns casos, 3-4 horas apos o inicio da dialise, a necessidade de uma terceira administração efectuada nas mesmas condições que as anteriores.ζ ζ ζ in some cases, 3-4 hours after the start of dialysis, the need for a third administration performed under the same conditions as the previous ones.
Foram efectuados um total de 1860 tratamentos de dialise, correspondendo a mais de dois meses de tratamento para cada doente.A total of 1,860 dialysis treatments were performed, corresponding to more than two months of treatment for each patient.
ΛΛ
Em todas estas experiencias, o Defibrotide confirmou, sem excepçõea, que era capaz de impedir a coagulação do sangue no circuito extra-corporal, e a tolerância foi considerada óptima em todos os doentes tratados.In all these experiments, Defibrotide confirmed, without exception, that it was able to prevent blood clotting in the extra-corporal circuit, and the tolerance was considered optimal in all treated patients.
Não se observaram quaisquer variações significativasNo significant variations were observed
Λ em relação aos seguintes parâmetros de hemocoagulação, determinados antes e depois da dialise:Λ regarding the following hemocoagulation parameters, determined before and after dialysis:
tempo de protrombina, tempo parcial de tromboplastina, fibrinogánio, anti-trombina III e reiracção do coagulo.prothrombin time, partial thromboplastin time, fibrinogen, anti-thrombin III and clot swelling.
A substância activa foi também objecto de testes preliminares para avaliar a possibilidade, como para a heparina,The active substance has also been the subject of preliminary tests to assess the possibility, as for heparin,
nua. Sob estas condições, contudo, verificou-se que □ Defibro tide não foi capaz de impedir totalmente a formação de coágulos .naked. Under these conditions, however, it was found that □ Defibro tide was not able to completely prevent the formation of clots.
Como precaução, foi então necessário administrar doses de heparina compreendidas, globalmente, entre 1200 e 2500 unidades.As a precaution, it was then necessary to administer doses of heparin between, globally, between 1200 and 2500 units.
Verificou-se, pelo contrario, que tal adição não e necessária para doses de Defibrotide superiores a 50D mg, de preferencia entre 600 e 800 mg.On the contrary, it has been found that such an addition is not necessary for doses of Defibrotide greater than 50D mg, preferably between 600 and 800 mg.
A partir do trabalho experimental acima descrito, tor na-se claro que o presente invento se refere ao processo para impedir a formação de coágulos no circuito extra-corporal do aparelho de dialise, e ao uso do Defibrotide num tal processo.From the experimental work described above, it is clear that the present invention relates to the process to prevent the formation of clots in the extra-corporal circuit of the dialysis apparatus, and to the use of Defibrotide in such a process.
363363
Ref: 88 OT 37 ERef: 88 OT 37 E
-10Mais especificamente:More specifically:
a) □ processo do presente invento e caracterizado pelo facto de pelo menos no inicio do tratamento de dialise se introduzir uma quantidade eficaz de Defibrotide no circuito extra-corporal a montante da membrana de diálise, simultaneamente com a entrada do sangue na circuito extra-corporal, sen do tal introdução inicial possivelmente seguida pela introdução de uma outra quantidade de Defibrotide.a) □ process of the present invention and characterized by the fact that at least at the beginning of the dialysis treatment an effective amount of Defibrotide is introduced into the extra-corporal circuit upstream of the dialysis membrane, simultaneously with the entry of blood into the extra-corporal circuit , with such an initial introduction possibly followed by the introduction of another quantity of Defibrotide.
b) De acordo com uma primeira concretização do presen te invento, a introdução inicial do Defibrotide e efectuada sob a forma de bolus, nomeadamente por uma so injecção, de preferencia a montante da bomba de circulação extra-corporal. De acordo com esta concretização a introdução inicial do Defibrotide contempla uma dosagem de cerca de 200 mg, sendo a mesma dose injectada 1,5-2 horas apos o inicio do tratamento de dialise.b) According to a first embodiment of the present invention, the initial introduction of Defibrotide is carried out in the form of a bolus, namely by a single injection, preferably upstream of the extracorporeal circulation pump. According to this embodiment, the initial introduction of Defibrotide contemplates a dosage of about 200 mg, the same dose being injected 1.5-2 hours after the initiation of dialysis treatment.
c) De acordo com uma segunda concretização do presente invento a introdução do Defibrotide e efectuada por infu/ são continua de uma dose de pelo menos 500 mg, iniciando-se a dita infusão simultaneamente com a introdução do sangue tirado do doente para o circuito extra-corporal. A' dosagem preferida do Defibrotide nesta segunda concretização e de 600-800 mg.c) According to a second embodiment of the present invention, the introduction of Defibrotide is carried out by continuous infusion of a dose of at least 500 mg, starting said infusion simultaneously with the introduction of blood drawn from the patient into the extra circuit -corporal. The preferred dosage of Defibrotide in this second embodiment is 600-800 mg.
d) De acordo com uma variante desta segunda concretização do processo do invento, a dosagem do Defibrotide é mantida a niveis mais baixos, da mesma ordem que os do processo da introdução de bolus”, com a adição cuidadosa de Heparina em doses reduzidas em 75% ou mais em relação as doses normalmente usadas no tratamento de dialise de acordo com a arte anterior, reduzindo obviamente de uma forma notável os inconvenientes conhecidos relacionados com o uso de heparina.d) According to a variant of this second embodiment of the process of the invention, the dosage of Defibrotide is maintained at lower levels, in the same order as those of the bolus introduction process ”, with the careful addition of Heparin in reduced doses by 75 % or more in relation to the doses normally used in the treatment of dialysis according to the prior art, obviously significantly reducing the known inconveniences related to the use of heparin.
e) D uso de Defibrotide, de acordo com o presente invento, contempla ó uso de composições que podem ser administradas por injecção ou infusão, como as descritas nos exeme) The use of Defibrotide, according to the present invention, contemplates the use of compositions that can be administered by injection or infusion, as described in the examples
363363
Ref:Ref:
OT 37 EOT 37 E
plos I e II abaixo.Examples I and II below.
Sem querer limitar indevidamente o presente invento, deve-se mencionar que, também na base do mecanismo de acção do Defibrotide ja conhecido e demonstrado, nomeadamente o desenvolvimento induzido no endotelio dos vasos por um activador de plasminogénio tecidular e por prostaciclina, era absolutamente impensável que o Defibrotide numa situação completamente diferente, como o e obviamente a que ocorre no circuito extra-corporal, fosse capaz de dar lugar ao fenómeno observado, o qual e o objecto do presente inventa.Without wishing to unduly limit the present invention, it should be mentioned that, also on the basis of the known and demonstrated mechanism of action of Defibrotide, namely the development induced in the endothelium of the vessels by a tissue plasminogen activator and by prostacyclin, it was absolutely unthinkable that Defibrotide in a completely different situation, such as the one that obviously occurs in the extra-corporal circuit, was able to give rise to the observed phenomenon, which is the object of the present invention.
Esta nova e surpreendente propriedade do Defibrotide é particularmente evidente no início da diálise, quando o san gue ao qual a solução de Defibrotide foi adicionada enche o aparelho.This surprising new property of Defibrotide is particularly evident at the beginning of dialysis, when the blood to which the Defibrotide solution has been added fills the device.
ΛΛ
Nesta situação, de facto, a substancia nas doses acima referidas, é capaz de impedir a coagulação do sangue sob condições nas quais o mecanismo de acção acima mencionado não pode evidentemente ser aplicado.In this situation, in fact, the substance in the doses mentioned above, is capable of preventing blood clotting under conditions in which the aforementioned mechanism of action cannot of course be applied.
As formas que podem ser usadas nesta nova aplicação do Defibrotide podem ser realizadas como frascos e composições lio, filizadas, alguns exemplos das quais estão descritos abaixo.The forms that can be used in this new application of Defibrotide can be made as flake bottles and compositions, some examples of which are described below.
EXEMPLO IEXAMPLE I
Composição do frascoBottle composition
EXEMPLO IIEXAMPLE II
Composição liafilizadaLyophilized composition
DefibrotideDefibrotide
SorbitolSorbitol
99
500 mg z500 mg z
363363
Ref: 88 OT 37 ERef: 88 OT 37 E
-12para ser diluído, aquando da utilização, com 10-15 ml de água destilada.-12 to be diluted, when used, with 10-15 ml of distilled water.
A descrição acima e especificamente referida ao Defibrotide; contudo e previsível que outras substancias de origem natural possuindo actividade fibronolítica e essencialmen. te isentas de actividade anticoagulante possam ter uso semelhante e são neste sentido contempladas pelo presente invento.The above description is specifically referred to Defibrotide; however, it is predictable that other substances of natural origin having fibronolytic activity and essentially. free of anticoagulant activity can have similar use and are contemplated in this sense by the present invention.
Claims (12)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22399/87A IT1223322B (en) | 1987-10-23 | 1987-10-23 | METHOD FOR PREVENTING THE FORMATION OF BLOOD CLOTS IN THE EXTRA-BODY CIRCUIT OF DIALYSIS EQUIPMENT USEFUL FOR IT |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PT88830B true PT88830B (en) | 1993-01-29 |
Family
ID=11195772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT88830A PT88830B (en) | 1987-10-23 | 1988-10-21 | PROCESS FOR THE PREVENTION OF FORMATION OF BLOOD COAGULATES IN THE EXTRA-CORPORAL CIRCUIT OF DIALYSIS AND COMPOSITION APPARATUS FOR THE SAME |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US4938873A (en) |
| EP (1) | EP0317766B1 (en) |
| JP (1) | JP2703582B2 (en) |
| AT (1) | ATE83936T1 (en) |
| AU (1) | AU611495B2 (en) |
| CA (1) | CA1313819C (en) |
| DE (1) | DE3877154T2 (en) |
| ES (1) | ES2037792T3 (en) |
| GR (1) | GR3006730T3 (en) |
| IT (1) | IT1223322B (en) |
| PT (1) | PT88830B (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2034285A1 (en) * | 1990-02-09 | 1991-08-10 | Masao Yafuso | Method and system for monitoring of blood constituents in vivo |
| US5286388A (en) * | 1991-06-20 | 1994-02-15 | Ingram John M | Method for neutralizing heparin in whole blood taken from an extracorporeal circuit |
| US5977083A (en) * | 1991-08-21 | 1999-11-02 | Burcoglu; Arsinur | Method for using polynucleotides, oligonucleotides and derivatives thereof to treat various disease states |
| US6514419B2 (en) * | 1994-09-16 | 2003-02-04 | Transonic Systems, Inc. | Method to measure blood flow and recirculation in hemodialysis shunts |
| US6153109A (en) | 1994-09-16 | 2000-11-28 | Transonic Systmes, Inc. | Method and apparatus to measure blood flow rate in hemodialysis shunts |
| US7670491B2 (en) * | 1998-10-20 | 2010-03-02 | Advanced Renal Technologies | Buffered compositions for dialysis |
| US6610206B1 (en) | 1998-10-20 | 2003-08-26 | Advanced Renal Technologies | Buffered compositions for dialysis |
| AU7607800A (en) * | 1999-09-22 | 2001-04-24 | Advanced Renal Technologies | High citrate dialysate and uses thereof |
| US6868739B1 (en) | 1999-10-19 | 2005-03-22 | Transonic Systems, Inc. | Method and apparatus to measure blood flow by an introduced volume change |
| US8771663B2 (en) | 2000-04-18 | 2014-07-08 | Gentium Spa | Formulation having mobilising activity |
| EP1147777A1 (en) * | 2000-04-18 | 2001-10-24 | Crinos Industria Farmacobiologica S.p.A. | Combination of defibrotide and G-CSF and its use to activate haematopoietic progenitors |
| US7351218B2 (en) | 2002-12-20 | 2008-04-01 | Gambro Lundia Ab | Device and process for extracorporeal treatment by citrate anticoagulant |
| ITMO20030293A1 (en) | 2003-10-29 | 2005-04-30 | Gambro Lundia Ab | DEVICE FOR THE DETERMINATION OF THE BLOOD FLOW IN AN EXTRACORPOREO CIRCUIT, AS WELL AS THE EQUIPMENT FOR BLOOD TREATMENT USING THE SAME DEVICE. |
| EP3026122A1 (en) | 2014-11-27 | 2016-06-01 | Gentium S.p.A. | Cellular-based method for determining the potency of defibrotide |
| CA3071544A1 (en) | 2017-08-03 | 2019-02-07 | Jazz Pharmaceuticals Ireland Limited | Formulations comprising a nucleic acid in a high concentration |
| KR20210008478A (en) | 2018-04-12 | 2021-01-22 | 재즈 파마슈티칼즈, 인코포레이티드 | Defibrotide for the prevention and treatment of cytokine release syndrome and neurotoxicity related to immune depletion |
| WO2020118165A1 (en) | 2018-12-07 | 2020-06-11 | Jazz Pharmaceuticals Ireland Limited | Subcutaneous delivery of high concentration formulations |
| EP4110287A1 (en) | 2020-02-28 | 2023-01-04 | Jazz Pharmaceuticals Ireland Limited | Delivery of low viscosity formulations |
| WO2021212055A1 (en) | 2020-04-17 | 2021-10-21 | Jazz Pharmaceuticals Ireland Limited | Defibrotide treatment for the prevention of organ rejection and injury |
| TW202308659A (en) | 2021-05-06 | 2023-03-01 | 愛爾蘭商爵士製藥愛爾蘭有限責任公司 | Defibrotide for the treatment and prevention of acute respiratory distress syndrome |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3899481A (en) * | 1970-11-03 | 1975-08-12 | Crinos Industria Farmaco | Process for the controlled partial degradation of deoxyribonucleic acid extracted from animal organs |
| DE2154279A1 (en) * | 1970-11-03 | 1972-05-25 | Crinos Industria Farmaco | Medicines for the fibrinolytic system |
| IT1043823B (en) * | 1970-11-03 | 1980-02-29 | Prephar | PROCEDURE FOR THE EXTRACTION OF NUCLEIC ACIDS FROM ANIMAL BODIES |
| US3946731A (en) * | 1971-01-20 | 1976-03-30 | Lichtenstein Eric Stefan | Apparatus for extracorporeal treatment of blood |
| JPS5226076B2 (en) * | 1972-10-06 | 1977-07-12 | ||
| US3809481A (en) * | 1972-12-01 | 1974-05-07 | Nasa | Single reflector interference spectrometer and drive system therefor |
| JPS5623961A (en) * | 1979-08-07 | 1981-03-06 | Kogyo Gijutsuin | Portable artificial kidney apparatus |
| JPS58180163A (en) * | 1982-04-16 | 1983-10-21 | 日機装株式会社 | Method and apparatus for preventing adhesion of blood corpuscle in blood purifier |
| JPS59183763A (en) * | 1983-04-04 | 1984-10-18 | 第一電気株式会社 | Blood dialytic method and apparatus reduced in amount to be used of blood anti-coagulant |
| JPS59197255A (en) * | 1983-04-22 | 1984-11-08 | 鐘淵化学工業株式会社 | Removing apparatus |
| IT1170214B (en) * | 1983-09-12 | 1987-06-03 | Crinos Industria Farmaco | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF PERIPHERAL ARTERIOPATHIES |
| IT1170215B (en) * | 1983-09-12 | 1987-06-03 | Crinos Industria Farmaco | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF STATES OF ACUTE RENAL INSUFFICIENCY |
| IT1206341B (en) * | 1984-02-16 | 1989-04-14 | Crinos Industria Farmaco | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ACUTE MYOCARDIUM ISCHHEMIA. |
-
1987
- 1987-10-23 IT IT22399/87A patent/IT1223322B/en active
-
1988
- 1988-10-20 EP EP88117485A patent/EP0317766B1/en not_active Expired - Lifetime
- 1988-10-20 DE DE8888117485T patent/DE3877154T2/en not_active Expired - Fee Related
- 1988-10-20 AT AT88117485T patent/ATE83936T1/en not_active IP Right Cessation
- 1988-10-20 ES ES198888117485T patent/ES2037792T3/en not_active Expired - Lifetime
- 1988-10-21 PT PT88830A patent/PT88830B/en not_active IP Right Cessation
- 1988-10-21 CA CA000580914A patent/CA1313819C/en not_active Expired - Fee Related
- 1988-10-24 AU AU24158/88A patent/AU611495B2/en not_active Ceased
- 1988-10-24 JP JP63266265A patent/JP2703582B2/en not_active Expired - Lifetime
- 1988-10-24 US US07/261,539 patent/US4938873A/en not_active Expired - Fee Related
-
1992
- 1992-12-31 GR GR920403117T patent/GR3006730T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US4938873A (en) | 1990-07-03 |
| ES2037792T3 (en) | 1993-07-01 |
| GR3006730T3 (en) | 1993-06-30 |
| DE3877154T2 (en) | 1993-04-29 |
| IT1223322B (en) | 1990-09-19 |
| CA1313819C (en) | 1993-02-23 |
| AU2415888A (en) | 1989-04-27 |
| ATE83936T1 (en) | 1993-01-15 |
| AU611495B2 (en) | 1991-06-13 |
| EP0317766B1 (en) | 1992-12-30 |
| IT8722399A0 (en) | 1987-10-23 |
| JPH0292363A (en) | 1990-04-03 |
| JP2703582B2 (en) | 1998-01-26 |
| EP0317766A1 (en) | 1989-05-31 |
| DE3877154D1 (en) | 1993-02-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| PT88830B (en) | PROCESS FOR THE PREVENTION OF FORMATION OF BLOOD COAGULATES IN THE EXTRA-CORPORAL CIRCUIT OF DIALYSIS AND COMPOSITION APPARATUS FOR THE SAME | |
| Henrich | Principles and practice of dialysis | |
| Hardaway et al. | Treatment of severe acute respiratory distress syndrome: a final report on a phase I study | |
| ES2254144T3 (en) | BETAINE GLYCINE FOR ANTITROMBOTIC USE. | |
| Diamond et al. | Nonanticoagulant protective effect of heparin in chronic aminonucleoside nephrosis | |
| Kobayashi et al. | Antithrombotic therapy with ticlopidine in chronic renal failure patients on maintenance hemodialysis-A multicenter collaborative double blind study | |
| US20080004225A1 (en) | New dialysis method | |
| Allen et al. | Some observations on bleeding tendency in thrombocytopenic purpura | |
| JPH0813742B2 (en) | Anticoagulant | |
| Bellomo et al. | Use of continuous haemodiafiltration: an approach to the management of acute renal failure in the critically ill | |
| Henny et al. | A randomized blind study comparing standard heparin and a new low molecular weight heparinoid in cardiopulmonary bypass surgery in dogs | |
| PT710483E (en) | USE OF SOME GLYCOSAMINOGLYCANS FOR THE PRODUCTION OF A MEDICATION FOR THE TREATMENT OF CHRONIC KIDNEY FAILURE | |
| Buck et al. | Effect of infusing fat emulsion into extracorporeal membrane oxygenation circuits | |
| Carr Jr et al. | Pain relief and clinical improvement temporally related to the use of pentoxifylline in a patient with documented cholesterol emboli—a case report | |
| US20070275086A1 (en) | Use of Increased Molecular-Weight Hirudin as an Anticoagulant in Extracorporeal Kidney Replace Therapy | |
| Radovanović et al. | Heroin addict with gangrene of the extremities, rhabdomyolysis and severe hyperkalemia | |
| Mustard et al. | Clinical experience with the artificial heart lung preparation | |
| Riess et al. | Rhabdomyolysis following cardiopulmonary bypass and treatment with enoximone in a patient susceptible to malignant hyperthermia | |
| Zhang et al. | Clinical experience with nadroparin in patients undergoing dialysis for renal impairment | |
| CN112755079A (en) | Medicine for preventing thrombosis or dissolving formed thrombus and preparation method thereof | |
| Baldree et al. | Intravenous desmopressin acetate in children with sickle trait and persistent macroscopic hematuria | |
| Ashouri | Regional sodium citrate anticoagulation in patients with active bleeding undergoing hemodialysis | |
| Kovalik et al. | Anticoagulation for the hemodialysis procedure | |
| RU2468760C1 (en) | Method of treating abdominal sepsis of bile origin, complicated by coagulopathy | |
| RU2343936C2 (en) | Method of hemodialysis at patients with risk of bleeding |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG3A | Patent granted, date of granting |
Effective date: 19920709 |
|
| MM3A | Annulment or lapse |
Free format text: LAPSE DUE TO NON-PAYMENT OF FEES Effective date: 19990131 |